title: Downregulation of the CXC chemokine receptor 4/stromal cell-derived factor 1 pathway enhances myocardial neovascularization, cardiomyocyte survival, and functional recovery after myocardial infarction.
abstract: OBJECTIVE
  Although adequate numbers of hematopoietic progenitor cells reside in the human bone marrow, the extent of endogenous neovascularization after myocardial infarction remains insufficient. The aim of this study was to identify the role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis in the mobilization and homing of hematopoietic progenitor cells in the ischemic heart.
  
  
  METHODS
  Human bone marrow-derived hematopoietic progenitor cells or saline were injected systemically into athymic nude rats 48 hours after myocardial infarction. Myocardial and bone marrow expression of stromal cell-derived factor 1 and chemotaxis of hematopoietic progenitor cells were measured in vitro in the presence or absence of stromal cell-derived factor 1. The role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis was investigated by means of antibody blockade or systemic administration of granulocyte colony-stimulating factor. Morphologic analysis included measurement of the infarct area, capillary density, and apoptosis, whereas left ventricular function was measured by means of echocardiographic analysis.
  
  
  RESULTS
  Expression of postinfarct stromal cell-derived factor 1 was increased by 67% in the bone marrow and decreased by 43% in myocardium. Disruption of bone marrow stromal cell-derived factor 1/CXC chemokine receptor 4 interactions by antibody blockade resulted in a redirection of human hematopoietic progenitor cells from the bone marrow to the ischemic heart and augmented neovascularization and cardiomyocyte survival. Similarly, systemic administration of granulocyte colony-stimulating factor to block CXC chemokine receptor 4/stromal cell-derived factor 1 interaction resulted in increased mobilization and homing of hematopoietic progenitor cells to the ischemic heart, which translated to augmented myocardial neovascularization, prevention of apoptosis, and improved cardiac function.
  
  
  CONCLUSIONS
  Bone marrow stromal cell-derived factor 1 upregulation after myocardial ischemia prevents mobilization of endogenous hematopoietic progenitor cells. We provide evidence that disruption of stromal cell-derived factor 1/CXC chemokine receptor 4 interactions allows redirection of hematopoietic progenitor cells to ischemic myocardium and enhances recovery of left ventricular function.
authors.affiliation: Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria. Nikolaos.bonaros@i-med.ac.at
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Bonaros
authors.forename: Hugo
authors.initials: H
authors.lastname: Sondermeijer
authors.forename: Dominik
authors.initials: D
authors.lastname: Wiedemann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schlechta
authors.forename: Thomas
authors.initials: T
authors.lastname: Schachner
authors.forename: Michael
authors.initials: M
authors.lastname: Schuster
authors.forename: Tetsunori
authors.initials: T
authors.lastname: Seki
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Martens
authors.forename: Silviu
authors.initials: S
authors.lastname: Itescu
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Kocher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001853:Bone Marrow / Q000378:metabolism; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D051381:Rats; D011923:Rats, Nude; D019718:Receptors, CXCR4 / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D046509:Tissue Culture Techniques; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor